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Gene Review

EDN1  -  endothelin 1

Ovis aries

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Disease relevance of PPET-1


High impact information on PPET-1

  • Smooth muscle cells (SMC) isolated from the main and midregion artery of control sheep confirmed these findings and showed higher levels of intracellular ET-1 synthesis in the main versus the midregion artery [1].
  • In main pulmonary artery and lung, ppET-1 transcripts fell to < 1% of controls [1].
  • We conclude that SMC from the main and midregion pulmonary artery are phenotypically different and suggest that local synthesis of ET-1 and TGF-beta, and increased levels of ET-1 in lung lymph, regulate ppET-1 gene expression and synthesis in arterial SMC during the development of air-induced CPH [1].
  • A semiquantitative reverse transcription PCR for ppET-1 gene expression was developed using ovine-specific primers [1].
  • CONCLUSIONS: These results, combined with prior studies, suggest that I/R causes reduced production of endogenous vasodilators (eg, nitric oxide), leaving unopposed the vasoconstriction that is caused by the continued presence of ET-1 [2].

Chemical compound and disease context of PPET-1

  • METHODS AND RESULTS: We measured plasma ET-1 concentrations by radioimmunoassay in isolated blood-perfused neonatal lamb hearts before and after 2 hours of 10 degrees C cardioplegic ischemia and examined the effects of ET-1 and the endothelin-A (ET-A) receptor antagonist BE-18257B on the postischemic recovery of isolated hearts [2].
  • We conclude that during sepsis, the NO scavenger PHP unmasks an underlying ET-1 mediated vasoconstriction, and its effect is antagonized by L-arginine and bosentan [6].
  • To investigate the role of endothelin-1 (ET-1), a potent vasoconstrictor produced by vascular endothelium, in HPVR an in vivo model of alveolar hypoxia was developed [7].
  • During U46619-induced pulmonary hypertension, both 4 Ala ET-1 (3.2% +/- 8.0 to 15.9% +/- 6.4, p < 0.05) and IRL 1620 (8.7% +/- 6.3 to 21.9% +/- 4.1, p < 0.05) produced selective dose-dependent decreases in PAP [8].
  • Phosphoramidon inhibits bET-1-induced hypertension, suggesting that the fetus possesses ET-1-converting enzyme activity [9].

Biological context of PPET-1

  • The ET-1 hearts showed significantly reduced recovery of LV systolic (positive maximum and volume-normalized dP/dt) and diastolic (negative maximum dP/dt) function, CBF, and myocardial oxygen consumption compared with controls (P < .05) [2].
  • Endothelin-1 (ET-1) is a potent constrictor of bronchial smooth muscle, but there is limited information on its actions on the airway mucociliary clearance in vivo [10].
  • ET-1 inhibited baseline mucin secretion (maximum inhibition: 60.3 +/- 4.2%, 50% inhibitory concentration: 0.8 +/- 0.17 nM) [11].
  • Twenty-four hours after exposing the cells to graded doses of ET-1 from 1 pM to 1 microM, cell number increased significantly over control in a dose-dependent manner [4].
  • 3. Thus in the late gestation ovine fetus endogenous ET-1 modulates basal FHR, CBF and CVR via ETA receptors [12].

Anatomical context of PPET-1

  • Importantly, infusion of BQ-123 or ET-1 distal to the common iliac artery did not affect PWV [13].
  • In the airways, ET-1 immunoreactivity and mRNA have been detected and localized to the epithelium, smooth muscle, and endothelium in different species, including humans [4].
  • In summary, ET-1, acting via ET(A)-receptors, inhibits baseline and ATP-stimulated mucin secretion from ovine airway goblet cells [11].
  • This binding was functional as ET-1 promoted mitogenesis of these muscle cells as measured by increased cell number in the absence of serum [4].
  • 1. We have proposed that contractile tension of the ductus arteriosus is sustained by a cytochrome P450-linked mechanism acting as a limiting step in the synthesis of endothelin-1 (ET-1) [14].

Associations of PPET-1 with chemical compounds

  • Decreased endothelial release of the vasodilator nitric oxide occurs after I/R, but the role of the endothelium-derived vasoconstrictor endothelin-1 (ET-1) in I/R is unknown [2].
  • The ET-1 effects were not influenced by pretreatment with either the cyclo-oxygenase inhibitor indomethacin or the leukotriene receptor antagonist MK-571, indicating that ET-1-induced depression in TMV does not involve the activation of prostanoids or peptide leukotrienes [10].
  • Big ET-1 contraction, unlike ET-1 contraction, was curtailed by the inhibitor of the ET-1-converting enzyme, phosphoramidon (50 microM) [15].
  • 5. ET-1 (0.1-10 nM) had no effect on isolated arteries precontracted with a thromboxane A2 (TXA2) analogue (ONO-11113) and treated with BQ123 (10 microM) [15].
  • Hypoxic tone is ascribed primarily to intramural generation of ET-1, while removal of the tonic action of a relaxant may only have an accessory role in the response [15].

Other interactions of PPET-1


Analytical, diagnostic and therapeutic context of PPET-1

  • In group 3 (n = 8), 10 pmol/L ET-1 was given just before the start of reperfusion [2].
  • Dose-response curves to intravenous infusion of ET-1 and phenylephrine were generated for pregnant and nonpregnant sheep [17].
  • The objective of the present study was to determine the role of nitric oxide (NO)-endothelin-1 (ET-1) interactions in the acute changes in pulmonary vascular tone after in utero partial constriction of the DA [18].
  • After 10 d of ductus arteriosus ligation, immunoreactive ET-1 content in whole lung tissue was 3-fold higher in hypertensive (n = 7) than control (n = 10) lungs (p < 0.05) [19].
  • Lung preproET-1 mRNA levels, tissue ET peptide levels, and cellular localization of ET-1 expression were determined by Northern blot analysis, peptide assay, and immunohistochemistry in distal lung tissue from fetal lambs between 70 and 140 days (term = 145 days), newborn lambs, and ewes [20].


  1. Regional variability in preproEndothelin-1 gene expression in sheep pulmonary artery and lung during the onset of air-induced chronic pulmonary hypertension. Participation Of arterial smooth muscle cells. Tchekneva, E., Quertermous, T., Christman, B.W., Lawrence, M.L., Meyrick, B. J. Clin. Invest. (1998) [Pubmed]
  2. Effects of endothelin-1 and endothelin-A receptor antagonist on recovery after hypothermic cardioplegic ischemia in neonatal lamb hearts. Hiramatsu, T., Forbess, J., Miura, T., Roth, S.J., Cioffi, M.A., Mayer, J.E. Circulation (1995) [Pubmed]
  3. Parathyroid hormone-related peptide may increase mammary blood flow. Davicco, M.J., Rouffet, J., Durand, D., Lefaivre, J., Barlet, J.P. J. Bone Miner. Res. (1993) [Pubmed]
  4. Endothelin-1 promotes mitogenesis in airway smooth muscle cells. Glassberg, M.K., Ergul, A., Wanner, A., Puett, D. Am. J. Respir. Cell Mol. Biol. (1994) [Pubmed]
  5. The endothelin A receptor antagonists PD 156707 (CI-1020) and PD 180988 (CI-1034) reverse the hypoxic pulmonary vasoconstriction in the perinatal lamb. Coe, Y., Haleen, S.J., Welch, K.M., Liu, Y.A., Coceani, F. J. Pharmacol. Exp. Ther. (2002) [Pubmed]
  6. L-arginine and endothelin receptor antagonist bosentan counteract hemodynamic effects of modified hemoglobin. Fischer, S.R., Traber, D.L. Shock (1999) [Pubmed]
  7. Pulmonary hypoxia increases endothelin-1 gene expression in sheep. Donahue, D.M., Lee, M.E., Suen, H.C., Quertermous, T., Wain, J.C. J. Surg. Res. (1994) [Pubmed]
  8. Endothelinb receptor agonists produce pulmonary vasodilation in intact newborn lambs with pulmonary hypertension. Wong, J., Vanderford, P.A., Winters, J., Soifer, S.J., Fineman, J.R. J. Cardiovasc. Pharmacol. (1995) [Pubmed]
  9. Systemic and pulmonary hemodynamic effects of big endothelin-1 and phosphoramidon in the ovine fetus. Jones, O.W., Abman, S.H. Am. J. Physiol. (1994) [Pubmed]
  10. Endothelin-1 depresses tracheal mucus velocity in ovine airways via ET-A receptors. Sabater, J.R., Otero, R., Abraham, W.M., Wanner, A., O'Riordan, T.G. Am. J. Respir. Crit. Care Med. (1996) [Pubmed]
  11. Endothelin-1 inhibits mucin secretion from ovine airway epithelial goblet cells. Clancy, S.M., Yeadon, M., Parry, J., Yeoman, M.S., Adam, E.C., Schumacher, U., Lethem, M.I. Am. J. Respir. Cell Mol. Biol. (2004) [Pubmed]
  12. The role of endothelin-A receptors in cardiovascular responses to acute hypoxaemia in the late gestation sheep fetus. Green, L.R., McGarrigle, H.H., Bennet, L., Hanson, M.A. J. Physiol. (Lond.) (1998) [Pubmed]
  13. Endothelin-1 regulates arterial pulse wave velocity in vivo. McEniery, C.M., Qasem, A., Schmitt, M., Avolio, A.P., Cockcroft, J.R., Wilkinson, I.B. J. Am. Coll. Cardiol. (2003) [Pubmed]
  14. Inhibition of the contraction of the ductus arteriosus to oxygen by 1-aminobenzotriazole, a mechanism-based inactivator of cytochrome P450. Coceani, F., Kelsey, L., Seidlitz, E., Korzekwa, K. Br. J. Pharmacol. (1996) [Pubmed]
  15. Involvement of endothelin-1 in hypoxic pulmonary vasoconstriction in the lamb. Wang, Y., Coe, Y., Toyoda, O., Coceani, F. J. Physiol. (Lond.) (1995) [Pubmed]
  16. Chronic intrauterine pulmonary hypertension increases preproendothelin-1 and decreases endothelin B receptor mRNA expression in the ovine fetal lung. Ivy, D.D., Le Cras, T.D., Horan, M.P., Abman, S.H. Chest (1998) [Pubmed]
  17. Mechanism of uterine vascular refractoriness to endothelin-1 in pregnant sheep. McElvy, S., Greenberg, S.G., Mershon, J.L., Yang, D.S., Magill, C., Clark, K.E. Am. J. Physiol. Heart Circ. Physiol. (2001) [Pubmed]
  18. Nitric oxide-endothelin-1 interactions after acute ductal constriction in fetal lambs. Ovadia, B., Bekker, J.M., Fitzgerald, R.K., Kon, A., Thelitz, S., Johengen, M.J., Hendricks-Munoz, K., Gerrets, R., Black, S.M., Fineman, J.R. Am. J. Physiol. Heart Circ. Physiol. (2002) [Pubmed]
  19. Chronic intrauterine pulmonary hypertension alters endothelin receptor activity in the ovine fetal lung. Ivy, D.D., Ziegler, J.W., Dubus, M.F., Fox, J.J., Kinsella, J.P., Abman, S.H. Pediatr. Res. (1996) [Pubmed]
  20. Developmental changes in endothelin expression and activity in the ovine fetal lung. Ivy, D.D., le Cras, T.D., Parker, T.A., Zenge, J.P., Jakkula, M., Markham, N.E., Kinsella, J.P., Abman, S.H. Am. J. Physiol. Lung Cell Mol. Physiol. (2000) [Pubmed]
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